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Postoperative delirium (POD), an acute cognitive dysfunction linked to morbidity and mortality, is characterized by memory impairments and disturbances in consciousness, particularly in patients aged 65 and older. Neuroinflammation and NAD+ imbalance are key mechanisms behind POD, leading to synaptic and cognitive deterioration. However, how surgery contributes to POD and neuroinflammation remains unclear, and effective treatments are lacking. Here we used a rodent model of bone fracture to examine the impact of surgery on synaptic plasticity, inflammation, and cognition. Additionally, we explored whether treatment with Nicotinamide (NAM), a NAD+ precursor, reduced the neuroinflammation and metabolic imbalance caused by surgery. Female C57BL/6J mice aged 20-22 months underwent tibial fracture surgery and received pre- and post-surgery NAM treatment. Neuroinflammation, synaptic plasticity, and cognition were assessed 72 hours post-surgery via long-term potentiation (LTP) assays, dendritic spine counting, and behavioral tests (open field maze and Y-maze). Tibial fracture surgery decreased LTP, dendritic spine density, and hippocampal-dependent memory function, and increased hippocampal inflammatory markers (IL-1 beta mRNA, CD38, and SIRT1 protein content); NAM pretreatment prevented these changes. Given surgery adverse effects on LTP and dendritic spine density, we assessed cellular oxidative state and BDNF protein levels. We found that surgery increased the oxidation of ryanodine receptor calcium channels (cellular redox sensors), and decreased BDNF protein levels; NAM supplementation mitigated both effects and prevented the cognitive decline and synaptic plasticity deficits while reducing inflammation post-surgery by lowering IL-1 beta and CD38 protein levels. We propose that the CD38 signaling pathway mediates these NAM protective effects., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Gerontological Society of America.)

Decoherence-free subspaces and subsystems (DFS) preserve quantum information by encoding it into symmetry-protected states unaffected by decoherence. An inherent DFS of a given experimental system may not exist; however, through the use of dynamical decoupling (DD), one can induce symmetries that support DFSs. Here, we provide the first experimental demonstration of DD-generated decoherence-free subsystem logical qubits. Utilizing IBM Quantum superconducting processors, we investigate two and three-qubit DFS codes comprising up to six and seven noninteracting logical qubits, respectively. Through a combination of DD and error detection, we show that DFS logical qubits can achieve up to a 23% improvement in state preservation fidelity over physical qubits subject to DD alone. This constitutes a beyond-breakeven fidelity improvement for DFS-encoded qubits. Our results showcase the potential utility of DFS codes as a pathway toward enhanced computational accuracy via logical encoding on quantum processors., (Creative Commons Attribution license.)

Aging compromises brain function leading to cognitive decline. A cyclic ketogenic diet (KD) improves memory in aged mice after long-term administration; however, short-term effects later in life and the molecular mechanisms that govern such changes remain unclear. Here, we explore the impact of a short-term KD treatment starting at elderly stage on brain function of aged mice. Behavioral testing and long-term potentiation (LTP) recordings reveal that KD improves working memory and hippocampal LTP. Furthermore, the synaptosome proteome of aged mice fed a KD long-term evidence changes predominantly at the presynaptic compartment associated to the protein kinase A (PKA) signaling pathway. These findings were corroborated in vivo by western blot analysis, with high BDNF abundance and PKA substrate phosphorylation. Overall, we show that a KD modifies brain function even when it is administered later in life and recapitulates molecular features of long-term administration, including the PKA signaling pathway, thus promoting synaptic plasticity at advanced age., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Ala Wai Canal is an artificial waterway in the tourist district of Waikiki in Honolulu, HI. Originally built to collect runoff from industrial, residential, and green spaces dedicated to recreation, the Ala Wai Canal has since experienced potent levels of toxicity due to this runoff entering the watershed and making it hazardous for both marine life and humans at current concentration, including Danio rerio (zebrafish). A community of learners at educations levels from high school to postbaccalaureate from Oahu, HI was connected through the Consortium for Increasing Research and Collaborative Learning Experiences (CIRCLE) distance research program. This team conducted research with an Investigator and team from Mayo Clinic in Rochester, MN, with the Ala Wai Canal as its primary subject. Through CIRCLE, research trainees sent two 32 oz bottles of Ala Wai- acquired water to a partnered laboratory at the Mayo Clinic in which zebrafish embryos were observed at differing concentrations of the sampled water against a variety of developmental and behavioral assays. Research trainees also created atlases of developmental outcomes in zebrafish following exposure to environmental toxins and tables of potential pesticide contaminants to enable the identification of the substances linked to structural defects and enhanced stress during Ala Wai water exposure experiments.

Objectives: To assess the feasibility of identifying fetal brain structures and anatomic landmarks included in the anterior complex (AC) and posterior complex (PC), as well as the proximal hemisphere (PH)., Methods: This was a prospective observational multicenter study of healthy pregnant women evaluated by ultrasound screening at 24 to 36 + 6 weeks' gestation. Six physicians performed transabdominal ultrasound, to obtain the planes required to visualize the AC, PC, and PH. Blind analysis by an expert and non-expert operator in fetal neurosonography was used to assess the structures included in each plane view., Results: In the population studied (n=366), structure detection rates for AC were over 95 %, with an agreement of 96 % when comparing expert and non-expert examiners. Visualization of the corpus callosum crossing the midline was detected in over 97 and 96 % of cases for the AC and PC, respectively, with an agreement of over 96 %. The PH plane, particularly through the posterior access via the mastoid fontanelle, enabled visualization of the proximal anatomical structures in almost 95 % of cases. Detection of the corpus callosum through the AC and PC, both proximal/distal germinal matrix (AC) and proximal Sylvian fissure through the anterior access (PH) in the 24-25 + 6, 26-31 + 6 and 32-36 + 6 weeks' gestation groups were successful in over 96 % of cases with high level of agreement., Conclusions: Inclusion of AC, PC, and PH later in pregnancy proves feasible with a high level of agreement between both expert and non-expert operators., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

The prevalence of quantum crosstalk in current quantum devices poses challenges for achieving high-fidelity quantum logic operations and reliable quantum processing. Through quantum control theory, we develop an analytical condition for achieving crosstalk-robust single-qubit control of multiqubit systems. We examine the effects of quantum crosstalk via a cumulant expansion and develop a condition to suppress the leading order contributions to the dynamics. The efficacy of the condition is illustrated in the domains of quantum state preservation and noise characterization through the development of crosstalk-robust dynamical decoupling and quantum noise spectroscopy (QNS) protocols. Using the IBM Quantum Experience, crosstalk-robust state preservation is demonstrated on 27 qubits, where up to a 3.5× improvement in coherence decay is observed for single-qubit product and multipartite entangled states. Through the use of noise injection, we demonstrate crosstalk-robust dephasing QNS on a seven qubit processor, where a 10^{4} improvement in reconstruction accuracy over alternative protocols is found. Together, these experiments highlight the significant impact the crosstalk suppression condition can have on improving multiqubit characterization and control on current quantum devices.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function., Competing Interests: Declaration of interests The authors declare that no conflicts of interest exist., (Copyright © 2023. Published by Elsevier Inc.)

Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3 C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3 C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3 C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3 C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system., (© 2021 MRC Laboratory of Molecular Biology. Published under the terms of the CC BY 4.0 license.)

Alzheimer's disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-β (Aβ) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aβ and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aβ pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aβ oligomers (Aβo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aβo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aβo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aβo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aβo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD., (© 2022. The Author(s).)

The 2019 coronavirus disease (COVID-19) is now a global pandemic. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative pathogen of COVID-19. Here, we study an in-host model that highlights the effector T cell response to SARS-CoV-2. The stability of a unique positive equilibrium point, with viral load V * , suggests that the virus may replicate fast enough to overcome T cell response and cause infection. This overcoming is the bifurcation point, near which the orders of magnitude for V * can be sensitive to numerical changes in the parameter values. Our work offers a mathematical insight into how SARS-CoV-2 causes the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2020 Elsevier B.V. All rights reserved.)

A series of 27 compounds of general structure 2,3-dihydro-benzo[1,4]oxazin-4-yl)-2-{4-[3-(1 H -3indolyl)-propyl]-1-piperazinyl}-ethanamides, Series I: 7 ( a - o ) and (2-{4-[3-(1 H -3-indolyl)-propyl]-1-piperazinyl}-acetylamine)- N -(2-morfolin-4-yl-ethyl)-fluorinated benzamides Series II: 13 ( a - l ) were synthesized and evaluated as novel multitarget ligands towards dopamine D 2 receptor, serotonin transporter (SERT), and monoamine oxidase-A (MAO-A) directed to the management of major depressive disorder (MDD). All the assayed compounds showed affinity for SERT in the nanomolar range, with five of them displaying K i values from 5 to 10 nM. Compounds 7k , K i = 5.63 ± 0.82 nM, and 13c , K i = 6.85 ± 0.19 nM, showed the highest potencies. The affinities for D 2 ranged from micro to nanomolar, while MAO-A inhibition was more discrete. Nevertheless, compounds 7m and 7n showed affinities for the D 2 receptor in the nanomolar range ( 7n : K i = 307 ± 6 nM and 7m : K i = 593 ± 62 nM). Compound 7n was the only derivative displaying comparable affinities for SERT and D 2 receptor (D 2 /SERT ratio = 3.6) and could be considered as a multitarget lead for further optimization. In addition, docking studies aimed to rationalize the molecular interactions and binding modes of the designed compounds in the most relevant protein targets were carried out. Furthermore, in order to obtain information on the structure-activity relationship of the synthesized series, a 3-D-QSAR CoMFA and CoMSIA study was conducted and validated internally and externally (q 2 = 0.625, 0.523 for CoMFA and CoMSIA and r 2 ncv = 0.967, 0.959 for CoMFA and CoMSIA, respectively).

Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.

Objective: To assess the feasibility of identifying structures included in anterior complex (AC) and posterior complex (PC), as well as a series of anatomic landmarks that could help to demonstrate the integrity of the cerebral proximal hemisphere (PH)., Methods: This was a prospective observational multicenter study of healthy pregnant women attending routine ultrasound screening at 20 + 0 to 33 + 6 weeks' gestation. Six physicians performed transabdominal (TA) ultrasound, in order to obtain the planes required to visualize the AC, PC, and PH. Blind analysis by a nonexpert and two experts in fetal neurosonography was used to assess the structures included in each plane view., Results: In the population studied (n = 747), detection of the structure rates for AC, PC, and proximal hemisphere was of 94%, 93%, and 96%, respectively, with an agreement of 97%, 94%, and 98% when comparing an expert and a nonexpert in fetal brain examiner. Detection of structures in the proximal hemisphere was significantly higher when observed through the proximal hemisphere plane rather than the transventricular plane., Conclusion: Our results suggest that inclusion of AC and PC complexes visualization, as well as real-time access to the proximal hemisphere, is feasible and could improve the prenatal detection of fetal cerebral anomalies., (© 2020 John Wiley & Sons, Ltd.)

Objective: To introduce visualization of the germinal matrix (GM), external angle of the frontal horn, and periventricular white matter while evaluating the anterior complex (AC) during basic ultrasound assessment of the fetal brain., Case Presentations: This is a retrospective observational study of healthy women with singleton pregnancies, with no increased risk of fetal central nervous system anomalies, attending routine ultrasound screening at 20-32 weeks' gestation. Seventeen cases are presented in which an abnormal aspect of the GM or external angle of the frontal horn or periventricular white matter on AC evaluation has allowed a prenatal diagnosis of peri-intraventricular hemorrhage, subependymal cysts, connatal cysts, periventricular venous hemorrhagic infarction, and white matter injury., Conclusion: An extended AC evaluation could significantly improve the -diagnosis of hemorrhagic/cystic/hypoxic-ischemic lesions during the performance of a basic ultrasound study of the fetal brain., (© 2020 S. Karger AG, Basel.)

Brain nicotinic acetylcholine receptors (nAChRs), a heterogeneous family of pentameric acetylcholine-gated cation channels, have been suggested as molecular targets for the treatment of alcohol abuse and dependence. Here, we examined the effect of the competitive nAChR antagonist UFR2709 on the alcohol consumption of high-alcohol-drinking UChB rats. UChB rats were given free access to ethanol for 24-h periods in a two-bottle free choice paradigm and their ethanol and water intake were measured. The animals were i.p. injected daily for 17 days with a 10, 5, 2.5, or 1 mg/kg dose of UFR2709. Potential confounding motor effects of UFR2709 were assessed by examining the locomotor activity of animals administered the highest dose of UR2709 tested (10 mg/kg i.p.). UFR2709 reduced ethanol consumption and ethanol preference and increased water consumption in a dose-dependent manner. The most effective dose of UFR2709 was 2.5 mg/kg, which induced a 56% reduction in alcohol consumption. Administration of UFR2709 did not affect the weight or locomotor activity of the rats, suggesting that its effects on alcohol consumption and preference were mediated by specific nAChRs., (Copyright © 2019 Quiroz, Sotomayor-Zárate, González-Gutierrez, Vizcarra, Moraga, Bermudez, Reyes-Parada, Quintanilla, Lagos, Rivera-Meza and Iturriaga-Vásquez.)

The effect of meal on blood glucose concentration is a key issue in diabetes mellitus because its estimation could be very useful in therapy decisions. In the case of type 1 diabetes mellitus (T1DM), the therapy based on automatic insulin delivery requires a closed-loop control system to maintain euglycaemia even in the postprandial state. Thus, the mathematical modelling of glucose metabolism is relevant to predict the metabolic state of a patient. Moreover, the eating habits are characteristic of each person, so it is of interest that the mathematical models of meal intake allow to personalise the glycaemic state of the patient using therapy historical data, that is, daily measurements of glucose and records of carbohydrate intake and insulin supply. Thus, here, a model of glucose metabolism that includes the effects of meal is analysed in order to establish criteria for data-based personalisation. The analysis includes the sensitivity and identifiability of the parameters, and the parameter estimation problem was resolved via two algorithms: particle swarm optimisation and evonorm. The results show that the mathematical model can be a useful tool to estimate the glycaemic status of a patient and personalise it according to her/his historical data.

Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0 mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8 mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2 mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2 mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10 mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In this work, hip and knee angles were decoded from low frequency EEG components recorded during the execution of two tasks. In order to compare their performance, three decoders based on multiple linear regression (MLR) models were applied under different conditions; which consisted in considering the processed data as a whole or divided into segments. Results suggest that, when the segments are related to specific tasks, the segmentation provides a better performance than applying the decoding method to unsegmented data.

With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with K i values of 20.3 ± 0.9 μM and 20.2 ± 0.9 μM, respectively. Kinetic inhibition assays showed non-competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues., (© 2018 Deutsche Pharmazeutische Gesellschaft.)

Reliability (accuracy, consistency and reproducibility) is a psychometric property, which is related to the absence of measurement error, or, to the degree of consistency and stability of the scores obtained through successive measurement processes with the same instrument. Thus a greater variability of results will lower the accuracy or reliability of instrument used, fact that is transverse from the laboratory to the clinical practice. It is determined by applying the reliability coefficient, which is the correlation between the scores obtained by the subjects in two parallel forms of a test. Assuming that the two forms of the test are parallel (measure the same), the scores of the subjects under study should be the same in both applications. In this way, when the correlation is 1, the reliability or precision is maximum. On the other hand, reliability could be influenced by the observer (the one that measures), the measuring instrument (by that with which it is measured), and by the observed (by what is measured). Therefore, the variability of each of these components must be taken into account when planning the measurement of the variable under study, in such a way to reduce measurement biases as much as possible. The most common ways to determine reliability are the models of parallel forms, test-retest and two halves. This manuscript focuses on the concepts of measurement and the various statistical techniques used for this, as a step prior to application in the clinic. Therefore, the aim of this manuscript is to generate a consultation document related to the reliability or reproducibility of the measurement process.

Objective: To describe a technique for the visualization and measurement of cerebral aqueduct diameter through a 2D sagittal median plane, and to report its aspect and measurement in fetuses with aqueductal stenosis (AS)., Methods: This was a cross-sectional study of 207 morphologically normal fetuses in low-risk pregnancies between 20 and 36 weeks of gestation. The cerebral aqueduct was visualized transvaginally in a midsagittal plane, and measurements of its greatest diameter (ampulla) were taken independently by an expert and a nonexpert sonographer. In addition, the aqueduct morphology from 7 fetuses with AS and complete follow-up were compared to the reference range., Results: Aqueductal measurements were obtained in 206 of 207 normal fetuses. Aqueductal growth occurred linearly with gestational age. Our method demonstrated excellent interobserver reproducibility. Among the 7 fetuses with AS, the aqueductal lumen could not be identified in 6 and had a funneling aspect in 1., Discussion: Our study demonstrated that it is possible to visualize and measure the cerebral aqueduct directly through a 2D ultrasound median plane. In fetuses with severe ventriculomegaly, the morphology and width of this structure could represent a relevant tool in improving AS diagnosis, differentiating it from other causes of significant ventricular dilation that carry a different outcome., (© 2017 S. Karger AG, Basel.)

A series of novel 3-indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin-1A receptor subtype (5-HT 1A R) and the 5-HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5-HT 1A R (K i  = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT (K i  = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug-target interactions, which allowed rationalizing the observed affinities., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Brain-Computer Interfaces (BCIs) for disabled people should allow them to use their remaining functionalities as control possibilities. BCIs connect the brain with external devices to perform the volition or intent of movement, regardless if that individual is unable to perform the task due to body impairments. In this work we fuse electromyographic (EMG) with electroencephalographic (EEG) activity in a framework called "Hybrid-BCI" (hBCI) approach to control the movement of a simulated tibio-femoral joint. Two mathematical models of a tibio-femoral joint are used to emulate the kinematic and dynamic behavior of the knee. The interest is to reproduce different velocities of the human gait cycle. The EEG signals are used to classify the user intent, which are the velocity changes, meanwhile the superficial EMG signals are used to estimate the amplitude of such intent. A multi-level controller is used to solve the trajectory tracking problem involved. The lower level consists of an individual controller for each model, it solves the tracking of the desired trajectory even considering different velocities of the human gait cycle. The mid-level uses a combination of a logical operator and a finite state machine for the switching between models. Finally, the highest level consists in a support vector machine to classify the desired activity.

Despite considerable research efforts, it is still not clear which mechanisms underlie neuronal cell death in neurodegenerative diseases. During the last 20 years, multiple pathways have been identified that can execute regulated cell death (RCD). Among these RCD pathways, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagy-related cell death, and lysosome-dependent cell death have been intensively investigated. Although RCD consists of numerous individual pathways, multiple common proteins have been identified that allow shifting from one cell death pathway to another. Another layer of complexity is added by mechanisms such as the endosomal machinery, able to regulate the activation of some RCD pathways, preventing cell death. In addition, restricted axonal degeneration and synaptic pruning can occur as a result of RCD activation without loss of the cell body. RCD plays a complex role in neurodegenerative processes, varying across different disorders. It has been shown that RCD is differentially involved in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), among the most common neurodegenerative diseases. In AD, neuronal loss is associated with the activation of not only necroptosis, but also pyroptosis. In ALS, on the other hand, motor neuron death is not linked to canonical necroptosis, whereas pyroptosis pathway activation is seen in white matter microglia. Despite these differences in the activation of RCD pathways in AD and ALS, the accumulation of protein aggregates immunoreactive for p62/SQSTM1 (sequestosome 1) is a common event in both diseases and many other neurodegenerative disorders. In this review, we describe the major RCD pathways with clear activation in AD and ALS, the main interactions between these pathways, as well as their differential and similar involvement in these disorders. Finally, we will discuss targeting RCD as an innovative therapeutic concept for neurodegenerative diseases, such as AD and ALS. Considering that the execution of RCD or "cellular suicide" represents the final stage in neurodegeneration, it seems crucial to prevent neuronal death in patients by targeting RCD. This would offer valuable time to address upstream events in the pathological cascade by keeping the neurons alive., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Heart failure (HF) is the leading cause of death worldwide. Efforts to decrease HF mortality rates include a multidisciplinary approach management. Although evidence suggests that this has been an optimal strategy for treating HF, the model remains not widely implanted. The current article explores the rationale behind the formation of a Heart Team in a developing country and its development despite the lack of an allocated budget., (© 2016 S. Karger AG, Basel.)

Amphetamine derivatives have therapeutic potential in diseases such as attention deficit hyperactivity disorder, narcolepsy and obesity. However, their prolonged use has been associated with cardiovascular toxicity and addiction. In recent years, we have studied the pharmacological effects of amphetamine derivatives such as methylthioamphetamine (MTA) and N,N-dimethyl-thioamphetamine, with the aim of improving their therapeutic selectivity. In this work, we show that similarly to MTA, N,N-dimethyl-thioamphetamine has effects on the dopamine system, producing a significant increase in extracellular levels of dopamine (as measured by in vivo brain microdialysis) and locomotor activity, which is a behavioural measure of dopaminergic activation. However, unlike MTA, N,N-dimethyl- thioamphetamine does not produce aortic contraction in vitro. Our results show that N,N-dimethyl-thioamphetamine is a drug that retains the dopaminergic effects of amphetamine derivatives but exhibits a lower potential for producing cardiovascular side effects., (© 2013 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Body nitrogen retention is dependent on the amount of dietary protein consumed, as well as the fat and carbohydrate content in the diet, due to the modulation of amino acid oxidation. PPARα is a transcription factor involved in the upregulation of the expression of enzymes of fatty acid oxidation. However, the role of putative PPARα response elements (PPREs) in the promoter of several amino acid-degrading enzymes (AADEs) is not known. The aim of this work was to study the effect of the synthetic ligand Wy 14643 and the natural ligands palmitate, oleate, and linoleate in rats fed graded concentrations of dietary protein (6, 20, or 50 g/100 g of total diet) on the expression of the AADEs histidase, serine dehydratase, and tyrosine aminotransferase. Thus, we fed male Wistar rats diets containing 6, 20, or 50% casein for 10 d. The results showed that addition of Wy 14643 to the diet significantly reduced the expression of the AADEs. Furthermore, the incubation of hepatocytes with natural ligands of PPARα or feeding rats with diets containing soybean oil, safflower oil, lard, or coconut oil as sources of dietary fat significantly repressed the expression of the AADEs. Gene reporter assays and mobility shift assays demonstrated that the PPRE located at -482 bp of the histidase gene actively bound PPARα in rat hepatocytes. These data indicate that PPARα ligands may reduce amino acid catabolism in rats.

Unlabelled: This article introduces the socio-demographic characteristics of psychosexual development and sexual crimes in men deprived of liberty for such crimes who are doing time in a Manizales prison (Colombia) in 2011. It also describes the differences between abusers of individuals under 12 years of age or who are 12 years old, and abusers of individuals over that age., Methodology: This is a descriptive, retrospective study performed by simple random sampling. It consisted of semi-structured interviews in which socio-demographic characteristics, psychosexual development, characteristics of crime, and prevalence of mental disorders were analyzed in a sample of 80 inmates convicted of sexual offenses at the Medium-security Pentientiary center in the city of Manizales. Univariate and bivariate analysis were performed using the χ(2) test and the logistic regression analysis with variables showing statistical significance in the bivariate analysis., Results: It was found that convicted sex offenders belong to lower socioeconomic levels, have low educational levels, and did not receive any sexual education. Such findings become more relevant when the crimes in questions are committed against 12-year-olders or children under this age., Conclusions: The lack of sexual education, low educational levels and lower socioeconomic levels are associated factors in the case of sexual offenses. It is important for society (particularly health-care institutions) to find additional measures for the criminalization of such behaviors in order to achieve a better control of the problem., (Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.)

4-Methylthioamphetamine (MTA) is a phenylisopropylamine derivative whose use has been associated with severe intoxications. MTA is usually regarded as a selective serotonin-releasing agent. Nevertheless, previous data have suggested that its mechanism of action probably involves a catecholaminergic component. As little is known about dopaminergic effects of this drug, in this work the actions of MTA upon the dopamine (DA) transporter (DAT) were studied in vitro, in vivo and in silico. Also, the possible abuse liability of MTA was behaviourally assessed. MTA exhibited an in vitro affinity for the rat DAT in the low micromolar range (6.01 μM) and induced a significant, dose-dependent increase in striatal DA. MTA significantly increased c-Fos-positive cells in striatum and nucleus accumbens, induced conditioned place preference and increased locomotor activity. Docking experiments were performed in a homology model of the DAT. In conclusion, our results show that MTA is able to increase extracellular striatal DA levels and that its administration has rewarding properties. These effects were observed at concentrations or doses that can be relevant to its use in human beings., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

Few studies have conducted morphological analyses of crocodilians, and little information exists on differences between size-classes and sexes in Neotropical crocodilians. In this study, we measured nine morphological traits in 121 captive Morelet's crocodiles Crocodylus moreletii (81 females and 40 males). Our results revealed that individuals < 2 m total length do not exhibit sexual dimorphism in morphometric characteristics. However, for crocodiles over 2 m in length, males were significantly larger than females in terms of dorsal-cranial length, cranial width, snout width and snout-ventral length. In general, morphological traits demonstrated a strongly significant relationship with total length at the smaller size class of 150-200 cm length. However, in the highest size class of 250-300 cm length (large adult males), morphological traits were no longer significantly related with total length. Male crocodiles demonstrated allometric growth of cranial morphology with significantly greater increase in cranial width, snout width, and mid-snout width relative to total length at higher size classes. Morphological dimorphism and allometric growth may be associated with adaptive strategies for reproductive success.

Background: The identification of clinical and pathological forms of Creutzfeldt Jakob Disease (CJD) started with the first cases of the disease. Genetic and biomolecular prion status assessment are allowing now a better classification., Aim: To identify the clinical forms of the disease that exist in Chile, based on clinical and neuropathological data., Patients and Methods: Review of records of 40 patients with CJD in whom a complete history, clinical details and neuropathological studies were available. Clinical aspects were grouped into five categories: behavioral and cognitive changes, sleep and alertness, visual impairment, motor disturbances, myoclonus and epilepsy. The neuropathological examination in each case allowed us to evaluate the damage of 13 areas of the central nervous system., Results: Five forms of CJD were identified. The classic form was present in 28 patients (70%), the Heidenhain form was present in five (12.5%), the ataxic form in four (10%), the form with Kuru plaques in two (5%) and the Vacuolar was present in one patient (2.5%)., Conclusions: The variety and forms of CJD in Chile do not differ substantially from those found abroad.

The transcription factor Nur77 has been identified as a neuronal activation marker of stressful stimuli in the central nervous system. Nur77 plays a key role at all levels of the hypothalamus-pituitary-adrenal axis during the stress response. However, the participation of Nur77 in extra-hypothalamic responses to stress is unknown. In this study, we studied the impact of acute and repeated immobilization stress on Nur77 expression in the bed nucleus of stria terminalis (BNST), a region involved in autonomic, neuroendocrine, and behavioral responses to stress. After a single session of immobilization stress we observed a significant increase of Nur77-like immunoreactivity in the BNST. This effect is not lost with repeated exposure to stress, since Nur77-like immunoreactivity and Nur77 mRNA in BNST were increased after the fifteenth stress session. The administration of desipramine, a specific inhibitor of noradrenaline reuptake, prevented the increase in Nur77-like immunoreactivity and mRNA induced by stress in rats subjected to repeated exposure to immobilization stress. Our results show that acute and repeated stress modulates Nur77 expression in BNST and suggest that Nur77 participates in extra-hypothalamic responses to stress.

The lateral septum is a brain nucleus involved in various mental disorders such as anxiety and drug addiction. In the present study, we investigated whether systemic amphetamine, known to release dopamine (DA) in nucleus accumbens, will also release DA in lateral septum. Our results show that systemic amphetamine administration (2 mg/kg i.p.) induced a significant increase in DA extracellular levels in nucleus accumbens but not in lateral septum. Interestingly, intralateral septum perfusion of amphetamine through the microdialysis probe induced a significant increase in DA extracellular levels. To test if GABAergic neurotransmission in lateral septum was responsible for inhibiting the release of DA when amphetamine was administered systemically, we perfused a GABA-B selective antagonist (CGP-52432) intra lateral septum. Systemic amphetamine administration induced a significant increase in lateral septum DA release when CGP-52432 was concomitantly superfused. Our results indicate that the systemic administration of amphetamine induces an increase in lateral septum GABA release and the consequent activation of GABA-B receptors counteracting the direct effect of amphetamine on lateral septum DA release., (© 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.)

Introduction: Tinnitus is usually associated with hearing loss, and patients with tinnitus and normal hearing are unusual. Neuro-otological findings have not previously been described in tinnitus patients with normal hearing., Aim: To analyse neuro-otological examination results from a group of tinnitus patients with normal hearing., Materials and Methods: Seventeen normal-hearing tinnitus patients seen over a 10-year period were retrospectively evaluated. Their results were compared with those of a control group of 17 normal subjects without tinnitus., Results: The main neuro-otological finding in the tinnitus patients was caloric test abnormality: a unilateral canal paresis was present in 15 of the 17 patients. Caloric tests were normal in 15 of the 17 control subjects., Conclusion: We may infer from these results that tinnitus could be the only clinical manifestation of a cochlear - and presumably cochleo-vestibular - lesion, and that unilateral canal paresis may be the only abnormal finding on neuro-otological examination.

Artificial Endocrine Pancreas (AEP) is one of the most optimistic approaches in Type 1 Diabetes Mellitus (T1DM) treatment due to the novel technological advances in continuous glucose monitoring, exogenous insulin delivery, and their proofs in clinical assessments. The main goal of AEP is to replace the pancreatic insulin secretion in the blood glucose regulation loop by means of an automatic exogenous insulin infusion. The joint element between glucose sensing and insulin delivering actions is an automatic algorithm-based decision. In this contribution, there is an H(infinity) control algorithm to compute the insulin infusion rate during hyperglycemia, exercise and nocturnal hypoglycemia. In order to mimic the insulin release pattern of a healthy pancreas, a frequency restriction in the insulin infusion pattern generated by controller was considered in the design. The inclusion of mathematical models of relations between glucose and chosen biosignals in the control loop generates an adequate insulin infusion pattern to compensate blood glucose variations during each metabolic scenario. The proposed automatic algorithm for decision shows good performance in controlling glycemia in metabolic scenarios, avoiding long-term hyperglycemia as well as glycemic disturbances during exercise and nocturnal hypoglycemia, guaranteeing insulin infusion with a delivery pattern closer to that generated by a healthy pancreas., (2009 Elsevier Ltd. All rights reserved.)

Compartmental-Physiological Models (CPM's) have been used to derive feedback controllers for the glucose regulation in Diabetes Mellitus (DM). Despite these important advances, there are two criticisms about the use of the CPM's in DM: (i) Can this class of model reproduce severe basal glucose levels (e.g., larger than 300 mg/dl)? and (ii) Does a CPM reproduce a distinct glucose level as its parameters change or is it unique even if its parameters change? This contribution aims these criticisms from the study of the parametric sensitivity of a CPM. The results exploit the analysis of the dynamic properties of the chosen CPM and permit to show that such model can reproduce distinct severe basal levels by modifying the values of the metabolic parameters, which agree with expectations on a realistic model. Mainly, the chosen CPM has been selected due to the following two reasons. (i) It includes the main organs related to the glucose metabolism in Type 1 Diabetes Mellitus (T1DM); as, for example, the liver, brain and kidney. (ii) It models metabolic phenomena as, for instance, the counter-regulatory effects by glucagon and the hepatic glucose uptake/production. Additionally, the chosen model has been recently used to design feedback controllers for the glucose regulation with very promissory results.

Urocortin 1, highly conserved metazoan gene of the corticotropin-releasing hormone family, is a simple gene structured in two exons and the corresponding intron. The urocortin 1 prepropeptide is entirely coded in the second exon. Preliminary non-isotopic in situ hybridization experiments with an oligonucleotide complementary to an intron sequence of the urocortin 1 gene showed a significant cytoplasmic-like staining, suggesting the occurrence of an intron-retained urocortin 1 transcript. This observation prompted us to study whether the urocortin 1 gene presents alternative splicing by intron retention event. Confocal fluorescent in situ hybridization for urocortin 1 RNA and the use of the specific DNA dye TOPRO-3 allowed us to show significant expression of the intron-retained urocortin 1 transcript that did not colocalize with TOPRO-3 staining indicating a cytoplasmic localization for the intron-retained urocortin 1 transcript. The natural occurrence of a polyadenylated intron-retained urocortin 1 RNA was further documented by reverse transcriptase polymerase chain reaction (PCR), primed with oligo(dT), of total RNA extracted from three brain regions, a midbrain region containing the Edinger-Westphal nucleus, cerebellum and prefrontal cortex. In the three brain regions studied, it was possible to amplify both intron-less as well as intron-retained urocortin 1 transcripts. The use of PCR primers that simultaneously amplify both urocortin 1 transcripts allowed us to show that the expression of both urocortin 1 transcripts differs among the brain regions analyzed, suggesting a tissue specific regulation of this alternative splicing. In silico analysis of the five known mammalian urocortin 1 genomic sequences showed high conservation of the urocortin 1 intron sequence. Further studies should investigate the regulation of this intron retention event and its consequence for the functionality of the urocortin 1 gene.

Autologous transplant of bone marrow stem cells (BMSC), although extremely useful after acute myocardial events, has not been evaluated in patients with old (>one-year-old) myocardial infarction. Our aim was to determine if CD34(+)-enriched peripheral-blood cells, obtained by apheresis, injected directly into the severely damaged myocardium of five patients with old myocardial infarction could restore depressed myocardial function. We found that 28 weeks after revascularization and peri-infarction injection of the enriched CD34(+) peripheral mononuclear cells, ventricular hemodynamic parameters that included left ventricular ejection fraction, left ventricular diastolic volume, ventricular systolic volume and left ventricular diastolic diameter approximated normal values and there was no restenosis; two patients have been followed for >52 weeks and their parameters are within normal values. In conclusion, intramyocardial injection of easily obtained CD34(+) enriched peripheral blood cells represent an encouraging procedure for patients with severely scarred and dysfunctional myocardium.

Aim: The aim of this study was to survey the information available regarding the N400 component of event related potentials (ERP) as an electrophysiological measure of semantic processing., Development: The N400 component of ERP is characterised, the advantages and disadvantages of studies that use this type of electrophysiological measures are presented, and the main findings of the experiments conducted in recent years to establish how N400 is related to linguistic processes are analysed. We also present some of the ways its study can be applied to understanding the brain processes underlying dementias, and especially Alzheimer s disease. The value of this component of ERP in the scientific study of mental processes is clearly illustrated., Conclusions: Electrophysiological measures of ERP are a very promising tool for the study of the cognitive processes that sustain the understanding and organisation of language and memory. ERP are changes in voltage that are registered on the scalp and which are synchronised with an observable (sensory, motor or cognitive) event. They are a non invasive method of monitoring brain processes in real time and as such can be used to obtain electrophysiological evidence of brain functioning and of psychological processes. The N400 component of ERP has been linked mainly to language processing and has been recorded in association with examples of semantic incongruence found in sentences, words or visually presented figures.

Background: Tuberculosis (TB) rates remain high in regions of Southern Mexico despite the existence of a National Tuberculosis Program. Understanding TB epidemiology in such settings would assist in the design of improved TB control and highlight the challenges confronting TB control in developing countries., Methods: We conducted a retrospective review of treatment control cards from 1991 to 1994 in five municipalities in a semiurban region of Southern Mexico., Results: The relatively high rate of TB observed, 42.6 per 100,000 inhabitants, did not change significantly during the study period. Cure rates among new cases were 79% and significantly lower among retreatment cases (62%). Directly observed therapy (DOT) was administered to 84% of patients. Approximately one-half of the retreatment cases who were not cured were compliant with therapy, suggesting that drug resistance contributed to these poor results. Of particular concern was a core group of 16 patients who had received at least three treatments., Conclusions: This region of Mexico has persistently high TB rates despite a DOT-based TB control programme which achieves an overall cure rate of 77%. There exist many retreatment cases for whom cure rates are significantly lower. These cases may serve as a core group for the dissemination of drug resistant TB. The control programme is being reinforced by a nominal register of patients, decreasing administrative barriers for drug supply to individual patients and the availability of mycobacteria cultures. In addition to these measures, in regions which are approaching the levels of efficacy recommended by the WHO it may be appropriate to consider focusing efforts on the identification and treatment of chronic cases.

Evaluators of family planning programs have begun to use simulated client ratings to assess the quality of services. However, little is known about the reliability of such ratings when they are used to assess individual provider performance. This study examined the reliability of quality-of-care ratings in a Peruvian community-based distribution program by using pairs of concealed observers--a simulated client and a companion. Average interrater agreement, measured by intraclass correlation, was .50, indicating that ratings are not reliable enough for the evaluation of a single provider by a single rater. The study results suggest that checklist-item scores referring to specific provider behaviors will be more reliable and useful than ratings.

With the massive vaccination campaigns with the inactivated poliomyelitis vaccine starting in 1955 and its oral presentation in 1961, this disease has been controlled in many countries. However, wild polio virus is still transmitted in many developing countries. The study reported in this article had the objectives of estimating the prevalence of antibodies against polio for three types of virus (1, 2 and 3) in the population from 12 to 59 months of age in Mexico and determining the factors associated with the absence of immunity. One section of the National Seroepidemiology Survey (NSS), a study with a representative sample of the Mexican population, included the analysis of 5,260 blood samples for polio seropositivity. These samples were processed using the technique of plaque-reduction-neutralization, with the cut-off for positive titer values at 1:8. The national immunity levels reported for the three types of polio virus were: type 1 (89.8%); type 2 (97.6%); and type 3 (85.4%). The state with the lowest seroprevalence was Campeche, with 59.7 per cent, and the highest observed was Baja California Sur, with 93.0 per cent. The NSS also showed that the immunity level increases with age. There were some differences observed by place of residence; seroprevalences were higher in the urban areas (type one, 93.4%; type two, 98.5% and type three, 88.2%) than in the rural zones (86.6%, 96.8% and 82.9%, respectively). As expected, previous vaccination with three or more doses, referred verbally by the parent or guardian of the child, was associated with higher positivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Measles is an illness of universal distribution and great social impact. According to the WHO, the annual deaths due to this disease amount to more than a million children in the world. The objectives of this paper are to estimate the seroprevalence of titer of antibodies to measles in the population of 12 to 59 months of age in Mexico and identify the determinants of the immunity state. From the National Seroepidemiology Survey, 5,232 blood samples of children between 12 and 59 months of age, were analyzed, their blood samples were considered positive when the antibody titers were greater or equal to 1:4, tested by hemagglutination inhibition using sensitized erythrocytes. The National seroprevalence was 76.2 per cent. By age group, an increment in positive level was observed age increased. The seroprevalence was 56 per cent in children of 12 to 24 month and 82 per cent for children 48 to 59 month of age. The history of vaccination was obtained verbally; 62.5 per cent of seropositive didn't have vaccination history and 82.5 per cent were of those vaccinated were positive. By place of residence, at rural level (populations less than 2,500 inhabitants) 74 per cent positives, compared to 79 per cent in children of urban areas. All risk factor were significant, based on a univariate analysis, being the one with greatest risk those with negative vaccine history and children of one year of age. The efficiency of the vaccine estimation was of 63.6 per cent. Risk factors related to the vinculation of immunity protection to measles or seropositives were age, and verbal history of vaccination.

The immune system has emerged as a major factor in the pathogenesis of Alzheimer's disease (AD). PANoptosis is a newly defined programmed cell death mechanism related to many inflammatory diseases. This study aimed to identify the differentially expressed (DE) PANoptosis-related genes with characteristics of immune dysregulation (PRGIDs) in AD using bioinformatics analysis of bulk RNA-seq and single-nuclei RNA sequencing (snRNA-seq) data. To improve the robustness of gene selection, we integrated 3 microarray and 6 snRNA-seq datasets from the Gene Expression Omnibus (GEO), which allowed us to not only examine overall gene expression patterns but also assess the cellular specificity of gene expression at the single-cell level. This approach helped to identify cell-type-specific gene alterations that may be masked in bulk RNA-seq analyses. Relevant PANoptosis, immune dysregulation, and AD-related genes were obtained from the Genecards database. The AlzData database was also used in this study. Expression validation, the least absolute shrinkage and selection operator (LASSO) regression model, and CytoHubba algorithms were applied for key DE-PRGIDs selection. LASSO, Logistic, and Cox regressions were used to construct prognostic models. The receiver operating characteristic (ROC) curve and correlation analyses were conducted on key DE-PRGIDs. The Seurat package in R software was employed for performing snRNA-seq data processing. Uniform manifold approximation and projection (UMAP) was utilized for cell type annotation and PRGID cell visualization. The violin plot was applied for displaying expression levels of PRGIDs. High-dimensional consensus weighted gene co-expression network analysis (hdWGCNA) was conducted on microglia to identify gene modules and hub genes. Venn diagram analysis identified 250 PRGIDs and 39 DE-PRGIDs. NFKBIA was identified as the key gene. Prognostic models based on the expression level of NFKBIA were obtained. ROC curve analysis revealed its area under the curve (AUC) value: 0.661 in training set and 0.836 in validation set. The heatmap displayed the result of correlation analysis. SnRNA-seq data analysis identified 7 cell types. The UMAP and violin plots revealed highly expressed PRGIDs in microglia with remarkable differences between healthy controls and AD. hdWGCNA identified PVT1 and APOE as hub genes associated with microglia. In conclusion, our findings provide evidence that PANoptosis may play a role in the immune dysregulation observed in AD. PVT1 has been implicated in AD pathogenesis, potentially exerting its effects through the miR-488-3p/FOXD3/SCN2A axis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a common progressive neurodegenerative disorder, and the vast majority of cases occur in elderly patients. Recently, the accumulation of Aβ and tau proteins has drawn considerable attention in AD research. This review explores the multifaceted interactions between these proteins and their contribution to the pathological landscape of AD, encompassing synaptic dysfunction, neuroinflammation, and PANoptosis. PANoptosis is a collective term for programmed cell death (PCD) modalities that encompass elements of apoptosis, pyroptosis, and necroptosis. The accumulation of Aβ peptides and tau proteins, along with the immune response in brain cells, may trigger PANoptosis, thus advancing the progression of the disease. Recent advancements in molecular imaging and genetics have provided deeper insights into the interactions between Aβ peptides, tau proteins, and the immune response. The review also discusses the role of mitochondrial dysregulation in AD. The exploration of the interplay between neurodegeneration, immune responses, and cell death offers promising avenues for the development of innovative treatments., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical Approval and Consent to Participate: This article does not contain any studies with human participants or animals. Consent for Publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: First, to assess whether levator ani deficiency (LAD) is associated with pelvic floor dysfunction 1 year postpartum, including urinary, vaginal and bowel symptoms; and second, to explore at what cut-off of LAD score such pelvic floor dysfunction arises., Design: Nested case-control study., Setting: Örebro University Hospital, Örebro, Sweden., Population or Sample: Primiparous women 1 year after vaginal birth., Methods: Three-dimensional endovaginal ultrasound assessment of the levator ani muscle; LAD score based on this ultrasound, and validated questions about pelvic floor dysfunction. Logistic regression models were used., Main Outcome Measures: Symptoms of pelvic floor dysfunction associated with LAD., Results: Altogether 190 women were included, 103 of whom were symptomatic cases and 87 asymptomatic controls. 53% in the case group, and 58% in the control group had a LAD score of 0. A greater LAD score was significantly associated with urinary incontinence (adjusted odds ratio [aOR] 1.11, 95% confidence interval [CI] 1.00-1.22) and vaginal laxity (aOR 1.14, 95% CI 1.03-1.25). The risk of urinary incontinence was increased when the LAD cut-off score was set between ≥ 1 point and ≥ 4 points. The risk of vaginal laxity was increased when the cut-off was set between ≥ 8 and ≥ 14 points., Conclusions: LAD was associated with both urinary incontinence and vaginal laxity. The risk of urinary incontinence increased already with minor LAD and defects of the most medial levator ani muscle portions normally supporting the midurethra may explain this increase., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Edaravone (Eda), a well-known free radical scavenger, has been reported as a possible therapeutic agent for ischemic stroke patients' recovery. This study aimed to investigate the effects of time-dependent treatment with Eda on medial prefrontal cortex (mPFC) ischemia. Mice were randomly allocated into six groups: control, sham, normal saline, Eda-I, Eda-II, and Eda-III. After induction of a photothrombotic ischemia in the mPFC region, Eda-I, Eda-II, and Eda-III groups received 3 mg/kg Eda intraperitoneally at the times of 0, 2, and 6 h post-surgery. After 1 day of recovery, the mice underwent behavioral tests (open field, novel object recognition, and T-maze). Next, necroptosis, NOD-like receptor protein 3 (NLRP3), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway-related protein levels were measured in the lesioned area using western blot analysis. For double confirmation, IL-1β and IL-18 were also assessed by immunofluorescence in the area. Further, histological evaluations were performed to measure tissue damage. The results showed that mPFC ischemia impaired recognition and spatial working memory without affecting locomotor activity, while immediate Eda administration improved cognitive impairments. Furthermore, acute Eda treatment reduced RIP1, RIP3, and MLKL levels, inhibited NLRP3 inflammasome proteins (NLRP3, ASC, and Cas1), decreased IL-1β and IL-18, upregulated Nrf2 and its targets (NQO-1 and HO-1), and diminished tissue damage. Our results highlighted the effects of acute administration of Eda post-stroke on improving cognitive impairments by suppressing necroptosis and NLRP3 inflammasome pathways and activating the Nrf2 antioxidant defense mechanism., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)